Process for the manufacture of 16-methylene steroids and compounds obtained thereby



United States Patent ice 3,178,462 PRGKIESS FQR THE MANUFACTURE OF lfi-WTH- YLENE STERGIDS COMPOS 0B- TAHNED HEREBY Karl-Heinz Bork, Griesheim, near Darmstadt, and Klaus Bruckner, Heinz-lurgen Mannhardt, Harald Metz, and Fritz von Werder, Darmstadt, Germany, assignors to E. Merck Alrtiengesellschaft, Darrnstadt, Germany No Drawing. Filed Sept. 1, 1960, Ser. No. 53,366 Claims priority, application Germany, Sept. 23, 1959, M 42,830 6 Uaims. (Cl. 260397.45)

Our invention relates to an improved process for the manufacture of l6-n1ethylene steroids having pronounced anti-infi-ammatory activity and to certain intermediates which are useful for the preparation of such steroids.

In the copending application of Mannhardt et 211., Serial No. 5,105, now US. Patent No. 3,074,977, there is described the preparation of 16-rnethylene-9u-halo-steroids oi the general formula:

CH ORr wherein R =H, OH (or or B) or =0; R =H or acyl; and X =F, C1 or Br; and which may contain a further double bond in the 1,2-p0sition.

These compounds are prepared from l6-methy-lene- Reichsteins Compound S by microbiological introduction of an l1-OH group and subsequent treatment with, for example, dehydrating agents, hypohalous acids, agents capable of splitting otf hydrogen halides, and H F We have found that the yields of 16-methylene-9a-halosteroids, and particularly the 9u-fluoro compounds, according to this invention, are improved if instead of 16- n1ethylene-Reichsteins Compound S the corresponding Zl-desoxy-derivative, 1G-methylene-17(x-hydroxy-progesterone, is used as starting material. Our researchers have shown that ll-hydroxylation of the progesterone derivative gives better yields than hydroxylation of compounds containing an OH or O-acyl group in the 2l-position.

The procedure according to the present invention is graphically illustrated by the following structural equations. i

3,178,462 Patented Apr. 13, 1965 HO :CHg

III

V VI 5 '1 tl OQU VIIIa,b

XIX XX dihydroXy-steroid (III or IV) thus obtained is treated by consecutive reactions with a dehydrating agent, iodine in an alkaline solution and subsequent reaction with an alkali acetate, a hypohalous acid, an agent splitting ofi hydrogen halides, and H F In any step of this synthesis a 1,2-double bond may be introduced. Thus steroids of the formula:

CHQOR --on HOfi Tom 1 1 B-HYDROXYLATION Curvularia lunata, Cunninghamella blakeslceana, Mucor griseocyanus, Cephalothecium sp., Trichothecium sp., Botrytis cinerea, Coniothyrium sp., Thamnidium sp., Streptomyces fradiae, Rhodoseptoria sp., Collectotrichum sp., Dothichiza sp., Absidia glauca, and Pycnoxporion sp.

1 lot-HYDROXYLATION Rhizopus (various species), Aspergillus (var. spec.), Penicilliurn (var. spec), Fusarium (var. spec), Neurospora sitophila, Trichothecium sp., Cephalotlzecium roseum, Pestalotia foedans, Dactylium dendroides, Heliocostylum piriforme, Thamnidium sp., Eurotium chevalierz', Muco javanicus and various other species, Delacroixl'a coronata, Absidia glauca, Cunninghamella echinulata, and further fungi of the Mucorales type.

Remarkably good yields are obtained when using fungi of the genus Fusarium or Penicillium because the starting material is completely converted, so that tedious separation procedures are avoided.

It is also possible to introduce the ll-OH group already into l6fl-methyl-l6a, 17oc-OXldO-PI'Og8St6IOII6, that is a precursor of the starting material used in the process of the present invention. The 16,17-0xido ring may be opened after the ll-hydroxylation by heating the compound in benzene with addition of catalytic amounts of a strong acid to form 16-methylene 11,17OL- dihydroxyprogesterone (III).

The ll-hydroxy-steroids may be dehydrated according to known methods to form the 9,11-unsaturated steroids. For the llp-hydroxy-steroids all usual transdehydrating agents are suitable, such as POCl or SOCI in pyridine. For llot-hYdl'OXY-StCI'OldS, all usual cisdehydrating methods are suitable, such as esterification of the lla-hydroxyl-group and subsequent elimination of the corresponding acid by a basic agent or by a thermal reaction.

The introduction of a ZI-acetoxy or other acyloxy group is possible in various reaction steps of this invention. The 11(m or [3)-hydroxy-steroids (III or IV), the 9,11-unsaturated steroids (V or VI) and the corresponding 9,11- oXido-steroids are suitable for this reaction. The steroid is treated with iodine in an alkaline solution and then with potassium acetate or other organic alkali metal salt.

e For example, the iodine is added to a solution of the steroid in a suitable sol-vent, such as a mixture of tetrahyd-rof-urane and methanol, and aqueous NaOI-I is added dropwise to the reaction mixture. The 21-iodo-compound thus obtained is reacted without isolation with potassium acetate or other salt to form the corresponding 21-acetoxy or other acyloxy compound.

To the 9,-11-do1rble bond of l6-methylene-4,9 1 1)-pregnadiene (VII) or of 16-methy1ene-1,4,9(11)-pregnatriene (VIII), .a hypohalous acid may be added, preferably HOBr or HOCl. The 1lp hydroxy=9a-chloroor 11;?- hydr-oxy-9aabromo steroids (IX or X) thus obtained may be converted into the corresponding 9,8,llfl-oxido compounds (XI or XII) by known methods, for example, by reaction with an alkali acetate.

By reaction of the 9&1 1,8-oxido compound (XI or XII) with H 1 the corresponding 9wfluoro-1lfi-hydroxy steroids (XIII or XIV) are obtained.

The compounds III and IV, IX and X, XIII and XIV may be oxidized to form the corresponding ll-keto compounds. A mixture of chromic acid and pyridine or a hypoihalous acid is a suitable oxidizing agent tor this reaction.

As will be evident from the reaction diagram, a double bond in the 1,2-position may be introduced at any stage of the process. Chemical as well as microbiological reactions are suitable for this dehydrogenation; A chemical dehydrogenating agent, for example, is SeO The reac- .tion is preferably carried out in a solution of tertiary butanol with small amounts of acetic acid. The mixture is u refluxed, the precipitated selenium separated, and the filtrate contains the compound dehydrogenated in the 1,2- position.

For the introduction of a double bond in the 1,2-position the following microorganisms are suitable: Bacillus sphaerz'cus, Fusarium solani, Corynebacterium simplex and hoagz'i, Alternaria sp., Mycobacterium smegmatis, Calon ectria decora, Mycobacterium lacticola, Ophiobolus sp., Alcani-genes sp. Didymella lycoperszci, Protaminobacter sp., Septomyxa afiinis, Nocardia sp., Cylindrocarpan radicicola, Streptomyces lavendulae, Bacillus cycl0- oxydans.

Depending on the microorganism, 4 to 14 hours are necessary for the fermentation. Particularly suitable are cultures of Bacillus sphaerz'cus var. fusz'formis and Corynebacterium simplex.

The products obtained according to this invention may be esterified if they contain one or more OH-groups, for example in the 11,17- and/or 21-position. For these reactionsthe following acids or their derivatives suitable tor esterification may be used: acetic acid and the homologues thereof, such as propionic, tert. butyl acetic, valeric and palmitic acids; o-lefinic acids like undecylenic acid; di-basic aliphatic acids like succinic acid and the homologues thereof; halogenocarboxylic acids such as cloroaceti=c acid; aminoand .alkylaminocarboxylic acids such as diethylamino acetic acid; phthalic and tetrahydrophthalic acids, amino-dicarboxylic acids such as aspartic acid; cyclopentylpropionic and cyclohexylpropionic acids; sulfuric acid, phosphoric acid, etc.

On the other hand, it is possible to saponify acyl groups present in the 11,17- and/or 21-position of the compounds prepared by the process of this invention. For this reaction, for example, an aqueous solution of NaHCO is suitable. Oxygen is preferably excluded from these reactions.

The starting material, 16- ethylene-17a-hydroxyprogesterone may be obtained in several Ways. For example, it may be prepared in an analogous manner to the process described in the above-mentioned copending application by heating 16p methyl 16a,17a oxido-pregnenolone or the 3-acetate thereof in benzene or in another inert solvent containing at least catalytic amounts of a strong acid, such as p-toluenesulfonic acid. Thus the 16a,17a-oxido ring is split to form l6-methyl-ene-17uhydroxy-pregnenolone. 16 methylene-l7a-hydroxy-pregnenolone or the 3-acetate thereof may be converted by treatment with a culture of F lavobaczerium dehydrogenans into 16-rnethylene-17a-hydroxyprogesterone. For Flavobacterium dehydrogenans a solution of a yeast extract (1%) in water, buffered to pH 7, is suitable as nutrient medium. The steroid compound is added to this culture after an incubation period of from 10 to 16 hours at 28 C.

16 3-methyl-16oz,17ot-oxido-pregnenolone may be converted into 16,8-methyl-l6oz,l7a-oxido-4-pregnene-3,20- dione also by an Oppenauer oxidation. The latter compound yields 16 -methylene17a-hydroxy-progesterone when heated with a strong acid in a neutral solvent like benzene. The 16fl-methyl-16a,l7a-oxido-pregnenolone and the 3-acetate thereof are obtained from 16-methyl- 5,l6-pregnadiene-3,8-ol-20-one 3-acetate.

1'6-methylene-17a-hydroxy-progesterone (I) may also be prepared by reaction of 16-methyl-4,16-pregnadiene- 3,20-dione with per-acids or with H 0 in the presence of a mild alkaline agent, such as K 00 resulting first in the corresponding :,L7oc-0Xid0 compound which is then converted into the desired starting material (I) by heating with a strong acid in benzene or other inert solvent.

The process according to the present invention represents an essential technical advance compared to the method of manufacturing 16-methylene-steroids proposed in US. Patent No. 2,865,808, according to which 9ot-fluoro-1G-methylene-prednisolone is prepared from 1 6u-hydroxyhydrocortisone in 14 steps, whereas according to the present invention the same compound is prepared from pregnadienolone-3-acetate in 11 steps. It should also be noted that the preparation of lda-hydroxyhydrocortisone from pregnadienolone-acetate itself requires 10 steps.

The l'6-methylene-corticoids obtained according to the present invention are useful as antiphlogistic drugs. They are suitable particularly for the treatment of rheumatoid arthritis and refractory allergies.

The invention is described in greater detail in the following examples which are presented for purposes of illustration only and not as indicating the limits of the invention.

EXAMPLE 1 9a-flucro-I6-methylene-hydrocortisoize (XIIIa) A. MICROBIOLOGICAL llcL-HYDROXYLATION OF I In a fermentation vessel 15 l. of a nutrient medium containing 3% saccharose, 1% malt extract, 0.1% yeast extract, 0.2% NaNO 0.1% KH PO 0.06% MgSO .7H O, 0.01% FeSO .7H O, buttered to pH 6.8, are inoculated with 750 ml. of a culture of Penicillium sp. (Collection E. Merck No. 2168). After a growth of 30 hours, 5 g. of l 6-methylene-l7a-hydroxy-progesterone dissolved in 300 ml. of methanol are added. The reaction is terminated after 15 hours. The solution is extracted with chloroform, the combined extracts are evaporated and the residue is washed with petroleum ether. The undissolved material is isolated and recrystallized from ethyl acetate. 16-methylene-4-pregnene- 11a,170a-diOl-3,20di011e (III) melts at 208-210. (00 8.4, A max. 24l-242 m E 462.

B. DEHYDRATION OF III 9.2 g. of 16-methylene-4-pregnene-l1a,17a-diol-3,20 dione are dissolved in 92 ml. of pyridine. 11.2 g. of p-toluenesulfonic acid chlorideare added with cooling and shaking. The mixture is allowed to stand overnight and is poured into aqueous HCl (5%) While being cooled With ice. The precipitate is sucked off, washed with water, dried and recrystallized from ethyl acetate. Melting point of the tosylate 162, (00 2 (chloroform). )r max. 229.5 m

11 g. of the tosylate in 125 ml. of acetic acid are refluxed for 30 minutes with 10.3 g. of anhydrous sodium acetate. The mixture is poured into water and the precipitated l6-methylene 4,9(11) pregnadiene-17a-ol- 3,20-dione (V) is sucked off and recrystallized from ethyl acetate. M.P. 227228. A max. 238-239 III/1., E 530, [e1 -23 (chloroform).

C. 21-ACEYLATION OF V To a solution of 4.6 g. of 16-methylene-4,9(11)-pregnadiene17a-ol-3,20-dione (V) in a mixture of 100 ml. of tetrahydrofurane and 12 ml. of methanol, 7.3 g. of iodine are added at Within 1 hour, an aqueous solution of NaOH is added dropwise until the colour of iodine has disappeared. After another hour, the solution is poured into water, the precipitate taken up with ether, the combined ether extracts are washed with water, dried and evaporated. The crude 21-iodo-compound is refluxed for 24 hours in 300 ml. of acetone with 13.5 g. of anhydrous potassium acetate. Then the solution is concentrated and water added. The precipitated 16- methylene 4,9(11) pregnadiene-17oc,21-diol-3,20-dione- 21-acetate (VIIb) is recrystallized from acetone or methanol. A max. 238 mu. M.P. 210212, [ot] +51 (chloroform);

Elfi 421 D. ADDITION OF H0131- TO VII 7.8 g. of 16-methylene-4,9(11)-pregnadiene-17ot,2ldiol-3,ZO-dione-Zl-acetate (VIIb) are dissolved in a mixture of 315 ml. of dioxane and 40 ml. of water. 4.55 g. of N-bromosuccin imide and 1.68 ml. of perchloric acid (70%) are added. After standing for 1 hour at room temperature, the solution is poured into water, the precipitate sucked off, Washed with water and dried. The crude 9a-bromo-16-methylene-hydrocortisone-2l-acetate (lXb) is used without further purification. A max. 243 mu.

E. ELIMINATION OF HBr FROM IX The crude 9a-bromo-16-methylene-hydrocortisone-21- acetate (IX) obtained according to Example 1D is dissolved in 450 ml. of ethanol. After addition of 19 g. of potassium acetate the mixture is refluxed for 2 hours, poured into Water and the emulsion thus obtained is extracted with chloroform. From these extracts the 96,115- oxido 16 methylene-4-pregnene-17a,21-diol-3,20-dione- 21-acetate (XIb) is obtained which is recrystallized from methanol. A max. 243 mu. M.P. 210-211; [e1 34.7 (dioxane);

E i 31... 390 F. SPLITTING OF THE OXIDO RING OF XI 4.3 g. of 913,115 oxido 16 methylene-4-pregnene 17a,21-diol-3,20-dione-21-acetate (XIb) are dissolved in 45 ml. of anhydrous chloroform and added at -60 C. to 25 ml. of a mixture prepared from 400 ml. of tetrahydrofurane, 150 ml. of chloroform and 250 g. of H 1 The mixture stands for 4 hours at -30, then 4 hours at 0 and is poured into a solution of NaHCO The emulsion is extracted with chloroform. Upon evaporation and recrystallization from acetone 9u-fluoro-16- methylene-hydrocortisone-Zl-acetate (XIIIb) is obtained. x max. 238 m M.P. 202404", [04 +17.4 (chloroform).

G. SAPONIFICATION OF XIII 1 g. of 9u-fluoro-16-methylene-hydrocortisone-2l-acetate (XIIIb) is dissolved in 50 ml. of methanol. While introducing N 2 ml. of a solution of K CO saturated with N are added. The mixture is stirred for 30 minutes at room temperature, neutralized with 1.7 ml. of acetic acid, diluted with water and extracted with chloroform. After evaporation 9m-fiuoro-16-methylenehydrocortisone (XIIIa) is obtained. A max. 238 my;

it... 49 M.P. 242 244; 00 +80 (dioxane).

8 EXAMPLE 2 16-metlzylene-4,9 (11 )-pregnadiene-17a-ol- 3,20-dione (V) A. MICROBIOLOGICAL llfi-HYDROXYLATION 15 l. of a nutrient medium prepared according to Example 1A are inoculated with 750 ml. of a culture of Curvularia lunata (Wakker) Boedijn. After growth of 18 hours at 28, 5 g. of 16-methylene-l7a-hydroxyprogesterone in 300 m1. of methanol are added. The starting material has disappeared after 24 hours. The solution is extracted with chloroform and evaporated. After treatment with petroleum ether and recrystallization from ethyl acetate 16-methylene-4-pregnenell}9,l7oc-diOl-3,20-Cll0n6 (III) is obtained. M.P. 216- 217", (00 +43 (chloroform); A max. 241-242 mg;

B. DEHYDRATION OF III 25.3 g. of 16-methylene-4-pregnene-11p,17oz-diol-3,20- dione (III) prepared according to Example 2A are dissolved in 300 ml. of pyridine. 4.25 ml. of SOC1 are added and the solution is heated to for 30 minutes. The mixture is poured into water, the precipitate sucked off, washed and dried. 16-methylene-4,9(1l)- pregnadiene-17ot-ol-3,20-dione (V) is recrystallized from ethyl acetate. M.P. 227, (a) 23 (chloroform).

EXAMPLE 3 9a-flu0ro-16-methylene-prednisolone (XIVa) A-l. MICROBIOLOGICAL 1,2-DEHYDROGENATION OF I In a fermentation vessel 15 1. of a nutrient solution containing 1% yeast extract (pH 6.8) are inoculated with 0.5 l. of a culture of Bacillus sphaericus. After 9 hours at 28, 8 g. of 16-methylene-4-pregnene-17a-o1- 3,20-dione (I) are added in 230 ml. of methanol. The dehydrogenation is terminated after about 25-3O hours. The solution is extracted with chloroform and 16-methylene-1,4-pregnadiene-17ot-ol-3,20-dione (II) is obtained from the combined extracts.

A-2. CHEMICAL 1,2-DEHYDROGENA'IION OF I 8.3 g. of l6-methylene-4-pregnene-l7a-ol-3,20-dione (I) are dissolved in cc. of dioxane and refluxed with 8.3 g. of 2,3-dichloro-5,6-dicyano-para-benzoquinone for 8 hours. The reaction mixture is diluted with chloroform, washed subsequently with water, 70 cc. of sodium hydroxide (1 n) and again with Water. By recrystallization from acetone/ether, the pure 16-methylene-1,4- pregnadiene-17a-o1-3,20-dione (II) is obtained.

B. MICROBIOLOGICAL 11-HYDROXYLATION or II According to Example 1A, 16-methylene-1,4-pregnadiene-l1e,l7u-diol-3,20-dione (IV) is prepared from II.

According to Example 2A, 16-methylene-1,4-pregnadiene-llfl,l7oc-diol3,20-di0ne (IV) is prepared from II. M.P. 230232 C. [0:1 -37.5 (chloroform).

C. DEHYDRATION OF IV According to Example 1B or 2B, 16-methylene-1,4,9 (1l)-pregnatriene-17e-ol-3,20-dione (VI) is prepared from IV.

D. According to Example 1C, 16-methylene-1,4,9(11)- pregnatriene-17a,21-diol-3,20-dione-2l-acetate (VIII) is prepared from VI.

E. According to Example 1D, 9a-bromo-16-methylene- 1,4 pregnadiene 1l,B,l7oc,21 triol 3,20 dione 21- acetate (X) is prepared from VIII.

F. According to Example 1E, 9,11-oxido-16-methylene 1,4 pregnadiene 17oc,21 diol 3,20 dione 21- acetate (XIIb) is prepared from X.

G. According to Example 1F, 9a-fluoro-l6-methyleneprednisolone-21-acetate (XIVb) is prepared from XII. M.P. 223-224"; A max. 238 my,

I 9 H. According to Example 16, 9a-fluoro l6-methyleneprednis'olone (XIVa) is obtained from XIVb by saponification. M.P. 246-248; (04) +26.6 (dioxane).

EXAMPLE 4 9oc-flu0r0-l6-mcthylene-prednisolone ZJ-acetate (XIVb) A-1. MICROBIOLOGICAL 1,2-DEHYDROGENATION OI XIII A-2. CHEMICAL 1,2-DEHYDROGENATION OF XIII According to Example 3A-2, 3 g. of 9u-fiuoro-l6-methylene-hydroc'ortisone-2l-acetate (XIIIb) are dehydrogenated. 9a fluoro 16 methylene prednisolone 21- acetate (XIVb) is recrystallized from acetone.

EXAMPLE 5 9oc-fluor0-16-methylene-c0rlisone (XVa) OXIDATION OF XIII 2.5 g. of 9a-fluoro-16-methylene-hydrocortisone-2lacetate (XIIIb) are dissolved in ml. of pyridine and added to a mixture of 2.5 g. of chromic acid anhydride and 25 ml. of pyridine. After 12 hours, the reaction mixture is poured into 250 ml. of ethyl acetate and refiuxed for 5 minutes. The precipitate is filtered with suction and washed with hot ethyl acetate. The filtrates are neutralized with diluted sulfuric acid, dried and concen trated. The crude 9ot-fluoro-16-rnethylene-cortisone-21- acetate (XVb) is recrystallized from methanol or ethyl acetate.

According to Example 16 the acetate (XVb) may be saponified to form 900 fiuoro 16 methylene cortisone (XVzz).

EXAMPLE 6 9a-flu0ro-16-methylene-prednis0lone 21 -acetate (XIV b) OXIDATION OF XIV According to Example 5, Ski-fluoro-l6-methylene-prednisolone-Zl-acetate (XIVb) is oxidized to form 9a-fluorol6-methylene-prednisone-acetate (XVIII The acetate XVII) may be saponified according to the procedure of Example 1G to form the alcohol XVIa.

EXAMPLE 7 9a-flu0r0-16-methyIene-prednisone (XVIa) 1,2-DEHYDROGENATION on XV According to Example 3A-1 or 3A-2, 7.5 g. of 90:- fluoro-l6-methylene-cortisone (XVa) are dehydrogenated to form 9a-fiuoro-16-methylene-prednisone (XVIa).

The acetate XVII) may be saponified according to Example 1G to form XVIa.

EXAMPLE 8 9ot-br0mo-16-methylene prednisone ZJ-acetate (XXb) A. PREPARATION OF XVII FROM III 2.3 g. of 16-methylene-4-pregnene-11a,17a-diol-3,20- di'one (III) are dissolved in 23 ml. of anhydrous pyridine. A mixture of 2.3 g. of chromic acid anhydride and 23 ml. of pyridine are added at 0. After 12 hours, the mixture is poured into 250 ml. of ethyl acetate. The precipitate is filtered with suction and washed with ethyl acetate. From the combined solutions 16-methylene-4- pregnene-l7a-ol-3,l1,20-trione (XVII) is crystallized.

In an analogous manner, 16-methylene-4-pregnene-1l5, 17a-diol-3,20-dione (III) may be oxidized to form 16 methylene-4-pregnene-17u-ol-3, 1 1,20-trione (XVII) B. PREPARATION OF XVIII FROM IV According to Example 5, or 8A, 16-methylene-1,4- pregnadiene-l7a-ol-3J1,20-trione (XVIII) may be prepared from IV (06- or fi-OH).

PREPARATION OF XIX FROM IX According to Example 8A, 9a-bromo-16-methylenehydrocortisone-Zl-acetate (IXb) may be oxidized to form 9u-bromo-16-methylene-cortisone-acetate (XIXb).

The acetate XIXb may be saponified to form XlXa according to Example 1G.

D. PREPARATION OF XX FROM X According to Example 8A, 9a-bromo-16-methyleneprednisolone-Zl-acetate (Xb) may be oxidized to form 9a-bromo-16-methylene-prednisone-2l-acetate (XXb).

The acetate XXb may be saponified to XXa according to Example 1G.

EXAMPLE 9 1 6-methylene-J ,4 -pregnad'iene-1 7 wall-13,1 J 20-tri0ne (XVIII) A-1. MICROBIOLOGICAL 1,2-DEHYDROGENATION OF XVII AND XIX According to Example 4A-1, 7.5 g. of 16-methylene-4- pregnene-17a.-ol-3,11,20-trione (XVII) are dehydrogenated. From the chloroform extracts l6-methylene-1,4- pregnadiene-lh-ol-ll1,20-trione (XVIII) is crystallized.

In an analogous manner XIXa may be dehydrogenated to form 9a-bromo-161methylene-1,4-pregnadiene-17a,21 diol-3,1 1,20-trione (XXa) A2. CHEMICAL DEHYDROGENATION OF XVII AND XIX 11 g. of l6-methylene-4-pregnene-l7a-ol-3,11,20-trione (XVII) are dehydrogenated according to Example 3A-2. The so formed l6-methylene-1,4-pregnadiene- 17a-O1-3,11,2Ut1'i0116 (XVIII) is filtered over silica gel.

In an analogous manner XIXb may be dehydrogenated to form 9a-bromo-16-methylene-l,4-pregnadiene-17a,21- diol-3,1 1,20-trione-21-acetate (30(1)) We claim 1. A member of the group consisting of a compound of the formula and the l-dehydro derivative thereof.

2. A member of the group consisting of a compound of the formula and the l-dehydro derivative thereof.

11 12 6. 16 methylene-1,4,9(11)-pregnatriene-17a1pha-o1-3, 72,915,433 12/59 Agnello et a1. .4. 16765 20-dione. 2,954,386 9/60 Beyler 260-397.47 References Cited by the Examiner 2,958,702 11/60 Taub et a1. 260397.45

UNITED STATES PATENTS 5 LEWIS GO'ITS, Primary Examiner. 2,602,769 7/52 Murray et a1. 19551 2,865,808 12/58 Agnello et a1. 16765 MORRIS LIEBMAN, LESLIE H. GASTON, Examiners. 

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 